GENETICS OF MICROANGIOPATHIC BRAIN INJURY Hypertension affects 50 million Americans and is the single greatest risk factor contributing to diseases of the brain, heart, and kidneys. Ischemic injury to subcortical white matter of the brain is a heritable complication of cerebral arteriolosclerosis associated with hypertension and stroke, and contributes to cognitive impairment late in life. The Genetic Epidemiology Network of Arteriopathy (GENOA) and the National Heart Lung and Blood Institute Family Blood Pressure Program (NHLBI-FBPP) are completing linkage and association analyses in multiple racial groups to characterize genes influencing blood pressure and the cardiac and renal complications of hypertension. This GENOA ancillary study will extend those efforts by identifying genes contributing to ischemic damage to the subcortical white matter of the brain, referred to as leukoaraiosis. Magnetic resonance imaging (MRI) of the brain will be used to non-invasively quantitate the volume of leukoaraiosis in already well-characterized African-American and non-Hispanic white GENOA sibships ascertained through hypertensive sibling pairs. Aim 1 will use variance components linkage methods to determine whether any of 387 polymorphic marker loci spanning the genome (already measured by GENOA) are linked to genes influencing the MRI volume of leukoaraiosis in more than 650 African-American and 650 non-Hispanic white GENOA sibling pairs. Aim 2 will use family-based association analyses to determine whether biallelic DNA polymorphisms in selected candidate genes, including those determined by GENOA to influence measures of blood pressure, also influence the MRI volume of leukoaraiosis in more than 700 African-American and 700 non-Hispanic white GENOA participants. Knowledge of genes that contribute to ischemic brain injury and predispose to cognitive impairment will improve understanding of the molecular basis of these disorders and lead to better methods of identifying and treating at-risk individuals who will benefit from early intervention.